Implementing genomic medicine in clinical care of deaf patients

在聋哑患者的临床护理中实施基因组医学

• 批准号: 9757749
• 负责人: XUE Z LIU
• 金额: $ 64.5万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-08 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757749
• 关键词: Address; Adult; Animal Model; Area; Attitude; Basic Science; Behavior; Bioinformatics; Biology; CRISPR/Cas technology; Candidate Disease Gene; Caring; Cell Therapy; Cells; Child; Clinic; Clinical; Clinical assessments; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; DNA; Data; Databases; Detection; Diagnosis; Diagnostic; Electrophysiology (science); Etiology; Family; Feasibility Studies; Foundations; Gene Expression Profiling; Genes; Genetic; Genetic Counseling; Genome; Genomic approach; Genomic medicine; Genomics; Genotype; Grant; Hair Cells; Health Status; Hearing; Human; Individual; Infrastructure; International; Knock-in Mouse; Knowledge; Laboratories; Labyrinth; Language Development; Mediating; Medical; Medical Records; Minority; Modeling; Molecular; Mus; Mutation; Nucleic Acids; Outcome; Participant; Patient Care; Patients; Phenotype; Physiology; Population; Procedures; Proteins; Protocols documentation; Quality of Care; Recovery of Function; Role; Sampling; Speech Development; Surveys; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Studies; Translating; Universities; Variant; accurate diagnosis; base; causal variant; clinical care; clinical database; clinical practice; cohort; cost effectiveness; database of Genotypes and Phenotypes; deaf; deafness; exome; experimental study; functional genomics; gene discovery; gene therapy; genetic deafness; genetic variant; genome editing; genome sequencing; genomic data; genomic profiles; genomic tools; genomic variation; hearing impairment; hearing restoration; hearing screening; human model; improved; in vivo; induced pluripotent stem cell; innovation; insight; next generation sequence data; normal hearing; novel; novel therapeutics; phenotypic data; pre-clinical; precision medicine; preclinical study; progenitor; repository; research clinical testing; screening; screening program; tool

Abstract: This continuing proposal will translate basic research utilizing high-throughput genomic approaches and functional genomics into routine diagnostic and therapeutic tools for non-syndromic hearing loss (NSHL), the most common type of hearing impairment in children and adults. We have developed a genomic variant detection platform MiamiOtogenomics - composed of MiamiCapitalArray/MiamiOtoGenes panels/exome (WES)/genome (WGS) and developed a genotype and phenotype database – MiamiGeneHeal. As shown in the preliminary data, we have already collected approximately 3,000 DNA samples with phenotypic data from a large international cohort (Miami Otogenetic Repository) of families with NSHL. Moreover, we have excluded all known HL genes in over 200 families, successfully identified more than 18 potential new candidate genes, created animal models for human HL, and have generated human iPSCs from patients with genetic deafness. We will build on these accomplishments and preliminary data by proposing to complete the following specific aims: 1. Apply an innovative genomics-based MiamiOtogenomics pipeline for NSHL; 2. Identify factors influencing the decision to pursue and act on genomic testing; 3. Initiate preclinical therapeutic experiments as a proof-of-concept for potential treatments for HL. The foundation of the proposal will leverage the exceptional genomics capacity of collaborators at the University of Miami into a genomic-based, minority-focused, diagnostic and treatment pipeline for HL. The overarching purpose of this application is to transit discoveries made in laboratory to patient care. This study will translate genomic analysis into clinical hearing screening to elucidate the exact molecular etiology for HL, which will enable more accurate diagnoses, better quality of care, more effective genetic counseling, as well as improved cost-effectiveness in medical care. In addition, we expect to contribute significantly to genotype-phenotype studies and to establish a robust framework for assessing long-term clinical outcomes. Moreover, this study will contribute to our fundamental understanding of HL. Finally, our innovative preclinical therapeutic experiments in our knockin mouse and human iPSC models using CRISPR will potentially discover new treatments for HL. This study will inform two important clinical aspects of precision medicine in USA populations, especially in USA minorities: general acceptance in clinical practice and clinical utility. We will perform one of the largest and most integrated clinical/genomic/functional/novel therapeutic studies on NSHL to date. Our prior results, the interdisciplinary team's expertise and our established study infrastructure and population access support feasibility of our Aims.

摘要：该持续提案将使用高通量基因组方法和 功能性基因组学成为非综合听力损失（NSHL）的常规诊断和治疗工具，这是最常见的 儿童和成人的听力障碍类型。我们已经开发了一个基因组变体检测平台 Miamotogenomics-由迈阿密二氧化碳/迈阿密生殖器图组成/外显子（WES）/基因组（WGS）和 开发了基因型和表型数据库 - 迈阿密黑核。如初步数据所示，我们已经 从一个大型国际队列（迈阿密耳遗传学）中收集了大约3,000个DNA样品。 NSHL家庭的存储库。此外，我们排除了200多个家庭中所有已知的HL基因 确定了18多个潜在的新候选基因，创建了人类HL的动物模型，并产生了人类 来自遗传死亡患者的IPSC。我们将通过提议提出这些成就和初步数据来主动 完成以下特定目的：1。将基于创新的基因组学基因组基因组学管道应用于NSHL； 2。 确定因素会影响追求和对基因组测试采取行动的决定； 3。启动临床前治疗实验 作为HL潜在治疗方法的概念。该提案的基础将利用卓越的基因组学 迈阿密大学合作者的能力成为基于基因组的，以少数群体为中心的，诊断和治疗的能力 HL的管道。本申请的总体目的是在实验室中对患者护理进行的过境发现。这 研究将将基因组分析转化为临床听力筛查，以阐明HL， 这将使更准确的诊断，更好的护理质量，更有效的遗传咨询以及改进 医疗保健的成本效益。此外，我们期望对基因型 - 表型研究产生重大贡献 建立一个可靠的框架来评估长期临床结果。此外，这项研究将有助于我们 对HL的基本理解。最后，我们在敲门蛋白小鼠中进行的创新临床前治疗实验 使用CRISPR的人IPSC模型可能会发现HL的新疗法。这项研究将告知两个重要的 美国人口中的精确医学的临床方面，尤其是在美国少数民族中：临床普遍接受 实践和临床实用程序。我们将执行最大，最集成的临床/基因组/功能/新颖 迄今为止，NSHL的治疗研究。我们先前的结果，跨学科团队的专业知识和我们既定的研究 基础设施和人口访问支持我们目标的可行性。